UC Irvine

Eukaryotic mRNA 3' processing is an essential step in the gene expression pathway and it is tightly coupled to many other cellular processes including transcription termination, splicing, mRNA export, and translation. As a result, it is under stringent regulation by many different factors such as viral infection, stress, and small molecule inhibitors. This study examines how mRNA 3' processing and transcription termination are regulated during herpes simplex virus 1 (HSV-1) infection and during treatment of JTE-607, a small molecule inhibitor. We found that HSV-1 and its immediate early factor ICP27 contribute to widespread changes in host mRNA alternative polyadenylation (APA) by activating intronic polyadenylation sites (PAS). We also discovered that the small molecule inhibitor JTE-607 inhibits mRNA 3' processing in a sequence-specific manner and the cleavage site region immediately following AAUAAA is the core sensitivity determinant of a PAS to JTE-607. A machine learning model that predicts the impact of JTE-607 on PAS selection and transcription termination genome-wide was developed. The findings of this study provide insights into the regulatory mechanism of mRNA 3' processing and transcription termination by viral infection and small molecule inhibitors, which shed light on targeting mRNA 3' processing as a novel strategy for broad spectrum anti-viral and anti-cancer therapeutics.